Percutaneous Implement and Method for Manufacturing

ABSTRACT

Micro implement with micro payload is used for painless and safe percutaneous drug delivery. The micro•head made of maltose or saccharide contains drug and stands on micro-stem installed in orifice of stem holder. Non drug micro-stem supports the payload to adjust insertion depth and reach an interest region under skin and is set to come out from the orifice just after insertion. The payload is completely bullet-like inserted into skin and the drug contained micro•head in the upper micro payload is also delivered into skin completely. The bioavailability 100% is accomplished. The inserted payload solves in internal water and releases drug around the interest region. The implement is composed of payload and holder. The payload is unified of micro•head with drug and non-drug micro•stem. All saccharides means ecologically disposable.

BACKGROUND

The present invention relates to percutaneous technologies formedications, cosmetics, material implantation for beauty, nutrition forhealth, drug delivery for deep organs under skin, and medical devicesand microneedle for dermal administration as the technologies in common,and also relates to a 3 dimensional molding micro processing technologyfor mounting a microneedle to a holder by registration controlledprecisely in 0.001 mm ground rule, and including fine transportationtechnology dealing with small drug chip or micro objects to manufacturethe devices.

Applicant(s) hereby incorporate herein by reference any and all patentsand published patent applications cited or referred to in thisapplication.

By way of background, microneedle technology for transdermal drugdelivery has been highly expected. The object is not restricted only toskin disease treatment, beauty treatment and beauty operation but alsopainless or non-invasive medical devices for treatment of immune systemdisease relating to regions in the depths of skin and entire body, butthe technology is actually behind the expectation because the progressof relevant technology is stagnating for uncertainty factors due toproduct and manufacturing technology. Simple and convenient microneedleaiming for a high level of drug delivery effectiveness is highlyexpected, and its product having function of drug delivery absolutelyallowed to reach inside the body with repeatable and reliable needlepart of accurate form and volume are highly expected.

Exactly dosing medical devices have been highly expected, andconventional manufacturing technologies of microneedles accommodating tothe expectations are resin-treated injecting molding, grinding work andbeam processing such as laser beam or synchrotron radiation X-rays, butthe common feature is restricted to the deformation processing of thesubstrate or the materials. Microneedles applied to conventional micromachine of less than 0.1 mm length mostly comes from substrate processwhich is restricted to the method influenced by material characteristicsof substrate like integrated electronic circuit. The method could end upin different feature far from requirement property. The followingreference shows a representative example of microneedles originated fromthe substrate deformation, but the quantitative dosage rate andconvenience was imperfect.

Subject on reliability that is quantitativity including bio availabilityat drug delivery is most important. There are administration methods bymeans of coat-type microneedles of inorganic or organic materialscoating drug on the side or the point, and of mix-type microneedlesmixing drug with internal solving materials. The coat-type microneedlescan hardly administrate the whole dose due to remove at injection, andthe mix-type microneedles can be hardly inserted the whole needle,therefore, a guarantee of dose quantitativity for precise delivery ofwhole drug is difficult.

In the mix type microneedles, useless drug leaked out to the substrateis avoidable by a means of manufacturing needles separately fromsubstrate and after that the needles are assembled on the substrate.Since errors of being incapable of insertion occur from uneven adhesivestrength, a part of drug left on the substrate is wasted. Microneedlesin the form of completely removing like a bullet have been sought.

Short needles less than 1 mm have been mainly manufactured because onlyskin has been targeted for the treatment. Application for the regions inthe deep part of the skin or entire body has lately increased includingimmune system and diabetes. Microneedles longer than 1 mm have beenexpected for painless administration targeting the deep regions.However, such drug mixed microneedles don't exit.

In microneedle separately manufactured the needle from the substrate,the installing method, which allows to carry and hand such a smallobject into a holder or a substrate as external diameter less than 1 mmand the length less than 5 mm, is needed. A difficult process thatmicroneedle formed a small and light object around 0.001 mg isindependently be conveyed and assembled into a holder is needed.However, there is not micro transportation technology and manufacturingtechnology to deal with light micro object less than 0.001 mg level.

Drug mixed transdermal microneedles made of degradable materialsfunctioned dissolving the materials and releasing the drug into skin butwe had an issue of low bioavailability or unstable quantitativity due toinsufficient injection without inserting whole needle up to needle rootinto skin. To solve the issue, needle tips are expected to definitely beinserted into skin surface and up to the needle root. The perfectinsertion is obtained by completely releasing needles from substrate inmedication by a structure of different material needle from substrateand automatically detaching needles from a substrate. Then, drug in theneedles are expected to be carried into skin completely. However, thestructure, with which a uniform size of needles were completely releasedand drug was delivered into skin with stable quantitativity andrepeatability, was not available. Furthermore, the detachable structure,with which had flexibility of needles were steadily fixed beforemedication and were completely released from substrate, was notobtained. We set subject on seeking the structure of the complete drugdelivery function.

We had only short length microneedles of less than 1 mm, sinceconventional microneedles were targeted only the skin for medication.Recently, the treatment targeting deep region or whole body is muchexpected especially about immune disease and diabetes and then longmicroneedles of longer than 1 mm are occasionally wanted to painlesslydeliver drug to deep regions. Since such long microneedles with mixeddrug were not realized, the function forming long microneedle is soughtas a subject.

Registration of fine ground rule at less than 0.01 mm pitch is necessaryfor assembly of micro head sized from 0.1 mm to 5 mm and micro stem aswell. There is not such a fine micro processing method for assemblingdrug chips or functional drug chips and mechanical structure for thefine assembly and registration are sought as a subject.

Aspects of the present invention fulfill these needs and provide furtherrelated advantages as described in the following summary.

SUMMARY

Aspects of the present invention teach certain benefits in constructionand use which give rise to the exemplary advantages described below.

The present invention solves the problems described above by providing apercutaneous implement and method of manufacturing. In at least oneembodiment, there is provided a percutaneous micro implement comprisingmicro payload mounting onto the orifice of a stem holder and having apyramidal micro-head made from water solvable material including drugwith a column micro-stem integrated under the micro-head.

In another aspect, the micro head comprises external tip radius of lessthan 0.01 mm, the length from 0.02 mm to 5 mm, external radius of thebase from 0.01 mm to 1 mm, and any other shaped as any of pyramid,selected from trigonal pyramid, tetragonal pyramid, half shell cone,half shell bullet, cone, bullet or polygonal pyramid.

In another aspect, the micro payload comprises the micro-head in theupper part, and pure micro-stem of the external radius from 0.01 mm to 1mm and the length from 0.02 mm to 5 mm made from water solvable materialwith the same shape of the micro-head base in the lower part.

In another aspect, the percutaneous micro implement is characterized bystructure having a pyramidal micro-head containing drug chips.

In another aspect, the micro-head structure as assembled comprises theshape of a pure or drug combining two half-shell cones, which is any ofa pure cone, a cone containing drug, a combination of pure half-shellcone and half-shell cone containing drug, a combination of drugcontaining half-shell cone and another drug containing half-shell cone,a quadrangular pyramid comprised of pure pyramid and drug containingpyramid, a quadrangular pyramid comprised of drug containing pyramid andanother drug containing pyramid, a combination of drug containingpolygonal pyramid and another drug containing polygonal pyramid allowedto be flat on the base when to put together.

In another aspect, the materials of the percutaneous micro implement ofdrug are characterized by maltose, pullulan, collagen, hyaluronic acidand any of other polysaccharide mentioned in claim 1 and claim 3 aswater solvable material, or composite material combined as necessary.

In another aspect, the percutaneous micro implement is characterized bybeing any of maltose or mixture with maltose mentioned in claim 1 andclaim 3 as water solvable material.

In another aspect, the percutaneous micro implement, which is any ofvitamins, hyaluronic acid, collagen, protein, DNA, other drugs,nutrient, supplement, cosmetic materials, antibody drug, in vivospecified pigment, in vivo specified metal, in vivo specified metaloxide, in vivo specified magnetic material, biological material, in vivomonitoring material, cell, extra cellular matrix material, or thecomposite as necessary.

In another aspect, the percutaneous micro implement is characterized bystoring any of drug chip, solidified composite material; mixture ofmaltose or other saccharide with any drug.

In another aspect, the percutaneous micro implement is characterized bythe stem holder comprising of maltose, pullulan, hyaluronic acid,cellulose, other saccharide, paper, wood, resin, metal or silk, andhaving a support with orifice accepting the micro-stem base, or havingplural supports arranged in a substrate.

In another aspect, a manufacturing method of the percutaneous microimplement is characterized by using a rectangular-solid micro-mold forthe pyramidal micro-head having inverse-shaped pyramidal dent coincidentwith the mold in planes and having one or more dent or recess on therectangular solid, to form a pyramidal and a half-shell pyramidalmicro-head with a half-shell cone and a half-shell bullet.

In another aspect, a manufacturing method of the percutaneous microimplement is characterized by a micro-mold for micro-stem withinverse-shaped prism dent or prism recess to fit the micro stem shape inthe surface of the rectangular solid forming the micro stem in any shapeof triangular prism, quadrangular prism, column, half-shell column.

In another aspect, a manufacturing method of the percutaneous microimplement is characterized by mounting a micro payload, integrated bycooling coagulation or drying solidification, into the stem holderorifice by applying pressure or ultrasonic vibration to form drugmaterial with thermo-plasticity or moist plasticity into a pyramidal orcone shape integrated by three parts of a micro mold for micro head, amicro mold for micro stem and a holder.

In another aspect, a manufacturing method of the percutaneous microimplement is characterized by having a simultaneous three dimensionalmobile function finely adjustable in the three directions of back andforth, right and left, and up and down and releasing gradually at speedpitch of 0.001 mm per second vertical to the micro mold surface, in thefine releasing process of the molds from formed object of the micro-headand the micro-stem.

Other features and advantages of aspects of the present invention willbecome apparent from the following more detailed description, taken inconjunction with the accompanying drawings, which illustrate, by way ofexample, the principles of aspects of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate aspects of the present invention.In such drawings:

FIG. 1A is a perspective schematic view of an exemplary micro implementapparatus, in accordance with at least one embodiment;

FIG. 1B is a perspective schematic view of the micro payload thereof, inaccordance with at least one embodiment;

FIG. 2A is a side schematic view thereof, in accordance with at leastone embodiment;

FIG. 2B is an exploded side schematic view thereof, in accordance withat least one embodiment;

FIGS. 3A-3C are side schematic views thereof as inserted into the skinin three operational modes, in accordance with at least one embodiment;

FIG. 4A is a side schematic view thereof having an alternate micro steminserted into the skin, in accordance with at least one embodiment;

FIG. 4B is a side schematic view thereof having a further alternatemicro stem inserted into the skin, in accordance with at least oneembodiment;

FIG. 5A is a perspective schematic view of an exemplary micro head, inaccordance with at least one embodiment;

FIG. 5B is a perspective schematic view of an alternate micro head, inaccordance with at least one embodiment;

FIG. 6A is a perspective schematic view of the micro head of FIG. 5A ona micro stem, in accordance with at least one embodiment;

FIG. 6B is a perspective schematic view of the micro head of FIG. 5B ona micro stem, in accordance with at least one embodiment;

FIG. 7A is a perspective schematic view of a further alternate microhead, in accordance with at least one embodiment;

FIG. 7B is a perspective schematic view of a further alternate microhead, in accordance with at least one embodiment;

FIG. 8A is a perspective schematic view of a further alternate microhead, in accordance with at least one embodiment;

FIG. 8B is a perspective schematic view of a further alternate microhead, in accordance with at least one embodiment;

FIG. 8C is a perspective schematic view of the micro head of FIG. 8A ona micro stem, in accordance with at least one embodiment;

FIG. 8D is a perspective schematic view of the micro head of FIG. 8B ona micro stem, in accordance with at least one embodiment;

FIG. 9 is a perspective schematic view of a further alternate microhead, in accordance with at least one embodiment;

FIG. 10 is a perspective schematic view of a further alternate microhead, in accordance with at least one embodiment;

FIG. 11A is a perspective schematic view of the intersection of threeplanes, in accordance with at least one embodiment;

FIG. 11B is a perspective schematic view of an exemplary micro mold asresulting from the intersection of three planes illustrated in FIG. 11A,in accordance with at least one embodiment;

FIG. 12A is a perspective schematic view of the micro mold of FIG. 11 Bnow with an exemplary holder in accordance with at least one embodiment;

FIG. 12B is a perspective schematic view of a further alternate microhead as formed in the micro mold of FIG. 12A, in accordance with atleast one embodiment;

FIG. 13 is a perspective schematic view of an alternate micro mold, inaccordance with at least one embodiment;

FIG. 14A is a perspective schematic view of a further alternate microhead, in accordance with at least one embodiment;

FIG. 14B is a perspective schematic view of a further alternate microstem as formed in the micro mold of FIG. 13, in accordance with at leastone embodiment;

FIG. 15 is a perspective schematic view of the micro head of FIG. 14A onthe micro stem of FIG. 14B, in accordance with at least one embodiment;

FIG. 16 is a perspective schematic view of an alternate micro implementcomprising the micro head of FIG. 14A and the micro stem of FIG. 14B asassembled as shown in FIG. 15, in accordance with at least oneembodiment;

FIG. 17 is a perspective schematic view of a further alternate microimplement comprising the micro head of FIG. 14A and an alternate microstem, in accordance with at least one embodiment;

FIG. 18 is a perspective schematic view of a further exemplary microimplement and micro mold, in accordance with at least one embodiment;

FIG. 19 is a perspective schematic view of a further exemplary microimplement, in accordance with at least one embodiment; and

FIG. 20 is a perspective schematic view of a plurality of exemplarymicro implements arranged on a substrate, in accordance with at leastone embodiment

The above described drawing figures illustrate aspects of the inventionin at least one of its exemplary embodiments, which are further definedin detail in the following description. Features, elements, and aspectsof the invention that are referenced by the same numerals in differentfigures represent the same, equivalent, or similar features, elements,or aspects, in accordance with one or more embodiments.

DETAILED DESCRIPTION

The micro implement as shown in FIG. 1A has structure being installedthe micro payload in FIG. 1B by inserting bottom end of the micropayload into the appropriate orifice on an upper surface of the stemholder 4 to fix the micro payload. Since the micro payload is integratedof the micro head 2 having the sharp tip 1 of triangular pyramidal orrectangular pyramidal on top with made from drug mixed saccharide andthe micro stem 3 shaped triangular or rectangular column with made frompure saccharide under the micro head, the micro implement cab bereleased in medication as shown in FIG. 2B. In addition, the microimplement allows to level target depth in skin such as coneeous layer 6,dermal layer 7, and organs under skin 8 by adjusting length of the microstem. Furthermore, plural pieces of the micro implements are able tostand on a substrate.

The micro implement installed the micro payload made from maltose or theother saccharide materials allows to painlessly insert into skin andkeep inserting to enough as deep level as touching stem holder and thenleave only the micro payload in skin by releasing from the stem holderas shown in FIG. 3B, after the micro implement is pulled out from skinat enough insertion as shown in FIG. 3A. Almost all the micro payload isinserted from tip to body in skin at complete insertion, though thebottom end of the micro stem fixed into the orifice of the stem holderis exposed in skin surface. Since the micro payload is constructed ofthe micro head mixed drug in the upper part and the micro stem in lowerpart, the micro head is completely inserted in skin. The micro head ofthe micro payload disappears with dissolving and releasing drug in skinwater in a few minutes like 3 minutes after insertion 9, 10 as shown inFIG. 3C, resulting that all drug is diffused in skin to generateinfiltration region 11 and 100% bioavailability is achieved as stabledrug deliver condition and quantity conservation. Drug deliveryspecification is clear.

The saccharide micro payload of short micro stem is targeted at onlyskin as shown in FIG. 4A and the micro payload for deep target as shownin FIG. 4B can deliver drug to deeper region than 1 mm at shallowest.The deep micro payload allows us to treat immune disease with vaccineand diabetes disease needed whole body circulation with insulin.Furthermore, the long micro implement itself becomes volume increase andup to 50 mm cube with expected sufficient amount drug, ranging indelivery amount at mile gram unit weight as equivalent to as treatingthe immune reaction and the insulin drug.

The micro payload integrated of the micro head 2 and the micro stem 3 isformed by the method of forming the micro head from maltose orsaccharides in condition of heating melt and cooling harden in the firstprocess with the micro mold for the micro head, the micro stem in thesame condition as the micro head in the second process with the micromold for the micro stem, and by the method of identically connecting thebase of the micro head and the upper surface of the micro stem withassembling both the micro mold in highly precise positioning. The formedproduct of the micro head mixed drug with a sharp tip is obtained bydetaching from the molds after the three processes. The half shell cone14 in FIG. 5A and the half shell bullet 15 in FIG. 5B is formed by thesame processes and assembly. Furthermore, the payload product of thehalf shell cone or half shell bullet is obtained with integrating halfshell column 16 by the same process and assembly as shown in FIG. 6A orFIG. 6B respectively. Here, the half shell cone is defined halffragmental solid cut through top of the cone and the half shell bulletis defined as well as the half shell cone.

The two half shell cones are assembled to makes a cone. The conicalmicro head can have a combining solid of the micro head of half shellcone 14 with contained drug and the micro head of half shell cone 17without drug as shown in FIG. 7. The conical micro head keeps wellinserting function supported by half shell cone without drug, even ifthe half shell cone with drug becomes malfunction due to softening bydrug mixture. In the other case, the conical micro head can have twokinds of drugs in the half shell cone with a drug and another half shellcone with another drug. In addition, the conical micro head 18 canduplicate drug amount by assembling two of the same half shell microhead with drug as shown in FIG. 8A and the duplicated bullet shapedmicro head 19 is formed as well as shown in FIG. 8B. The micro payloadinstalled the conical micro head with integrated the column micro stem20 as shown in FIG. 8C. The micro payload installed the bullet shapedmicro head is formed as well as shown in FIG. 8D. In extension, themicro payload contained a drug chip inside the bullet shaped micro headis formed as shown in FIG. 9 or becomes the micro the pentagonalpyramidal micro head by combining triangular pyramid and rectangularpyramid as shown in FIG. 10.

In conventional microneedles, needles are directly connected tosubstrate and needle roots are left after only half tip side of needlesare inserted in medication, resulting in bioavailability of less than70% but more than 30% is lost as waste potion. In the micro implementwith preferred embodiment of the invention having the micro payloadmixed drug inlayed in the micro stem, drug in the micro payload iscompletely carried into skin, resulting in 100% bioavailability.

Though conventional transdermal microneedles are unstable inbioavailability due to changeable volume of microneedles inserted intoskin every medication, the micro payload with preferred embodiment ofthe invention is stable because the micro payload is completely releasedfrom the stem holder with the micro stem. Then, bioavailability isdirectly equaled to the volume and shape of the micro payload and isconstant every medication with repeatability.

Though conventional microneedles are shorter than 1 mm and do not reachdeep region under skin at all, the micro implement with preferredembodiment of the invention installed the micro payload with length ofmore than 1 mm can be manufactured by the micro mold delivers drug tofar deep region under skin and the length itself increases the volumewith increasing drug amount, resulting in effective treatment for immunedisease and diabetes, which cannot be treated by conventionalmicroneedles.

Conventional microneedle, which is obtained from substrate byprocessing, is needed to manage waste after medication with heavy worksdue to residual substrate having residual part of needles. In the microimplement with preferred embodiment of the invention, the micro payloadis completely transported into skin with released from the stem holder,leaving only substrate and stem holder after medication. The residualwaste, which is substrate of saccharides without touching skin, does notneed a special waste management meaning effective cost reduction. In thecase of all saccharide stem holder and substrate, waste of the microimplement after medication becomes dissolvable completely, solvingenvironmental issues.

Micro payload installed in the micro implement is an integration of drugmixing amorphous maltose micro head with shaped a variety of pyramidslike triangular or quadrangular and adhered on a column micro stem madefrom pure maltose for depth adjustment. In case of treating shallowregion in skin like coneeous layer, micro stem is not needed and themicro head itself works as a micro payload. In deep treatment underskin, the micro payload is an integration of the micro head and themicro stem. The micro head is any pyramidal shape having identical baseto the upper surface shape of the micro stem with a sharp tip in lessthan 0.01 mm at external radius and 0.01 mm to 5 mm length. The microstem is a column at length from 0.2 mm to 5 mm for the depth adjustmentand has sectional external radius from 0.01 mm to 0.5 mm.

In the micro implement form, the micro payload installed into an orificeon the upper surface of the stem holder is integrated a variouspyramidal shaped micro head with a sharp tip and a micro stem for depthadjustment, the micro payload functions a microscopic medical device toinsert into skin such as microneedles for percutaneous drug delivery.Drug is mixed in amorphous maltose or other saccharide and the microimplement made from the maltose or the saccharide dissolves by the waterin skin or body just like a micro drug capsule. The micro payload withinstalled a drug mixed maltose or saccharide micro head completely comesout from the holder orifice in medication or insertion, staying in skinand then the dissolving micro head releases the drug in the skin bydiffusion and infiltration. In any case of vitamins, hyaluronic acid orcollagen is selected as a drug, the micro implement, which is integratedamorphous maltose or other saccharide micro head with mixed drug atconcentration from 10% to 90% on a pure micro stem installed in theorifice of the stem holder, is manually inserted into skin. Then themicro payload comes out from the holder and the micro head perfectlyinserts in the skin like a bullet, allowing the whole drug to stay inskin. The micro head with mixed anything of vitamins, hyaluronic acid orcollagen is optimally formulated so that the head dissolves anddisappears in body internal water with delivering it into skin at 100%bioavailability.

The micro implement is a dermal drug delivery device characterized bymixing drug in the micro head. The principal ingredient mixing in themaltose micro head are pullulan, polysaccharide, collagen, hyaluronicacid or the complex. The tip of the head sizes less than 0.01 mm atexternal radius. The length of the head sizes from 0.02 mm to 5 mm. Thebase of the head sizes external radius from 0.02 mm to 5 mm. The headshapes any pyramid, quadrangular pyramid, a half-shell cone, ahalf-shell bowling-pin, polygonal pyramid, or a cone or bullet bymatching half-shells manufactured with micro molds. Drug chip containingmicro head has a form like shown in FIG. 9.

The micro stem, which is the lower part of micro payload of microimplement, is aimed at inserting the micro head in skin deeply andsystemic drug like insulin, hormone, or prostaglandin is useable. Thematerial is preferably identical to the micro head so that maltose,pullulan, other saccharide, hyaluronic acid, collagen, or the complex isappropriate. Any other material in vivo affinity dissolved safely inskin like chitin and chitosan, or biodegradable materials like polylactic acid is usable as the candidate.

Regarding shape of micro-mold of the micro-head, the tip size of themicro-head is the most important for medication or insertion function todeliver percutaneous drug and forming the micro-head mold 28 to sharpena micro-head tip is important too. Method of sharpening the tip of apyramidal micro-head is principally optimized to derive the minimum sizeof intersection 27 from cross cutting among three planes of the firstplane 24, the second plane 25 and the third plane 26. The micro headpyramid is a replica released from the identical dint opened in themicro mold. The tip 1 of the pyramid is originated from the tip 29 ofthe pyramidal dint by the method with a preferred embodiment of thepresent invention and the dint tip is touched on the upper surface ofthe mold. There are three planes in the dint of the micro-mold to formthe three planes of the pyramid of the micro-head, corresponding thefirst plane and the second plane of micro-head to two sides in the dintof the micro-mold and corresponding the third plane of the micro-head toopen triangle on the upper surface of the micro-mold. The optimizedmanufacturing method with a preferred embodiment of the presentinvention is making planarization of melted maltose poured into the dintas the third plane by sweeping to make the third plane and sharpen thetip of the micro-head.

Regarding the micro implement manufacturing method with preferredembodiment of the invention having the micro head or the micro payloadwith mixed drug, while the case of triangular pyramidal micro head isassumed, the mold 28, having the dint of lied triangular pyramid or morethan 2 the pyramidal dints identical to inversed the pyramidal microhead opened in stainless cuboid mold fitting the base arranged onto themold sidewall and upper surface of pyramidal dint is coincided to theupper surface of the cuboid, is prepared. Drug mixed viscous maltosesoftened by heating or drug mixed poly saccharides in dilution is pouredinto the dints in the mold, which has open bases of the triangularpyramidal dints in side wall of the mold and the open bases are closedwith the hold 30 attached to the sidewall of the mold. The two surfacesof triangular pyramidal micro head are corresponding to the two surfacesof the pyramidal dint in the mold and the upper surface of the mold headis processed by sweeping over flowing maltose and surface planarizationto level the surface at the upper surface of the mold in heating. Afterprocessing, the micro head is cooled down in the mold to be hardened andis pulled out from the mold to be formed. In the case of using the microhead as a micro payload without micro steam, the micro head is preciselymoved to the lateral direction by 0.001 mm unit digital control toremove and the pyramidal micro payload is made as shown in FIG. 12B. Inthe case of forming the micro payload integrated the drug mixed microhead and the micro stem, the micro head is held after its formation inthe first process and is connected the base of the micro head to the endof the micro stem in the second process with heating or wetting, afterthe micro stem is formed with the micro mold 31 in FIG. 13 for the microstem 32 in FIG. 14 in the second process. The micro payload issequentially is detached with the precise mechanism from the micro moldfor micro stem and from the micro mold for micro head. Here, the preciseremoving is defined as form of micro processing technology whichfunctions to shake up and down, right and left and forth and back inthree dimensional degree of freedom in order to detach the micro headfrom the micro mold with precise adjustment at 0.001 mm pitch. Inaddition, an easy detachment is obtainable if necessary vibration orultrasonic waves are applied to both the micro molds by appropriatepower ranged from 1 W to 10 W. In addition, the two micro molds as shownin FIG. 18 is allowed to drive with flexibility of three directions by0.001 mm unit and be heated and cooled simultaneously. Furthermore, themanufacturing method allows to make the micro implement of any long stemlike short stem in FIG. 16 or that of long stem in FIG. 17.

The micro implement with preferred embodiment of the present inventionallows to include pure solid medicine, complex medicine mixed thematerial of the micro head, micro capsule included medicine, and microcapsule included micro magnetic granule or micro electromagnetic granuleas drug chip 33 in the micro head 34 in FIG. 19. The drug chip formsellipsoid, rectangular or polygonal pyramid of the material selectablefrom the following materials: vitamins, collagen, hyaluronic acid,protein, DNA, medical agent, nutrient, supplement, cosmetic material,antibody test agent, pigment, metal, metal oxide, or the mixture, orthat of mixture selected from the upper materials in weight ratio from10% to 90%.

The stem holder, which installs the micro payload in the micro implementwith preferred embodiment of the present invention, is fulcrum havingorifice inserted the base of the micro payload i.e. the base of themicro stem. The micro stem is stably inlayed onto the orifice of thestem holder in store and has to be completely released from the orificewhen the micro payload is inserted into skin. Then, the micro stem isappropriately installed in the stem holder by slightly pushing it intothe orifice in 3% smaller than the base of the micro payload withapplication of vibration or ultrasonic waves ranged in 1 kHz to 10 kHz.In addition, the long stem holder shaped like a stick is easy to handlein the case of a micro payload. Multiple of the micro payloads are linedup in array or a pin support and multiple of the stem holders formstanding on the substrate in FIG. 20. Since material of the holder istouched the skin at insertion of the micro payload but is taken offafter use, the material doesn't require safety as strictly as in vivoresidue. Any of saccharide, paper, wood, resin, metal, maltose,pullulan, hyaluronic acid, cellulose, solid protein, silk or biomaterial or the complex can be the material. Saccharide, however, ispreferable in perspective of reducing the waste disposal cost.

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofthe disclosed subject matter. These examples are intended to be a meresubset of all possible contexts in which the percutaneous implement maybe utilized. Thus, these examples should not be construed to limit anyof the embodiments described in the present specification, includingthose pertaining to the various percutaneous implements and/or methodsand uses thereof. Accordingly, the practical examples explainedhereinafter do not limit the invention.

EXAMPLE 1

A micro implement was installed a micro payload. The payload wasintegrated of a 0.003 mm tip sized, 0.7 long and 0.25 mm bottom sidequadrangular pyramidal micro-head in up part and a 0.5 mm long and 0.25mm wide cubic micro-stem in down part. The micro-head is made ofamorphous Maltose with mixed 17% Sodium Ascorbic acid and Rhodamine 6B.The micro-stem is made of pure Maltose. In human skin medication byusing 100 pieces micro implements arrayed on a substrate by 10 rows and10 columns, 100% the drug was transferred into skin by recognizing thecolor of Rhodamine 6B. The bio availability 100% resulted.

EXAMPLE 2

By using bullet shaped micro-head of 1 mm length and 0.2 mm bottomdiameter including two 50 k-100 k molecular weight Hyaluronic acid 0.01mm side long cubic chips with impregnated Rhodamine 6B, the chip wasinserted and completely transferred into skin. Skin surface regionaround the inserted chip became swollen.

EXAMPLE 3

Micro implement sample installed micro head with mixed Lidocaine, one oflocal anesthetic drug, was made by a metal micro mold having 20 hollowsof a triangular pyramidal micro-head of 1 mm length in a side line ofstainless metal. The sample was used for animal test. Rat wasadministrated and blood plasma was sampled in leg, arm, stomach, back,and neck, resulting that 0.003-0.01 mg Lidocaine was detected in theplasma.

EXAMPLE 4

0.01 mg Insulin was obtained in a micro implement installed in a 3 mmstem holder having a micro payload integrated a pyramidal micro head of3 mm length with mixed 50% Insulin from bovine pancreas in Maltose and 2mm length Maltose micro-stem. 1 mg Insulin was transferred into bodywith a 100 micro implements by 10 rows and 10 columns in a medication. 1mg Insulin is equaled to 26 IU. A diabetes patient who needs 60 IU in aday is three times provided enough in morning, noon and night with 80micro implements in a cassette, while 60 IU is equivalent to 2.3mg. 1 mgInsulin including micro implement deserves diabetes medical treatment.

EXAMPLE 5

A sample of micro payload integrated a 1 mm length conic micro-head withdrug and 2 mm length micro-stem without drug was injected in rat. Theconic micro-head was matched a half-shell Maltose cone mixed 1 mgAlprostadil derived from Prostagladin and a half-shell Maltose conemixed Rhodamine 6B. The color of Rhodamine 6B was recognized in ratwhole body with 20 mmHg hypotension indicating vasodilation fromAlprostadil.

EXAMPLE 6

A sample of 2 mm length micro implement installed a bullet shapedmicro-head contained a 2 mg hyaluronic acid chip mixed 1 mg Collagenextracted Collagen solution from human fibroblasts was used for ananimal trial with rat. 50% Collagen was transferred into skin.Aggregating Collagen was recognized in intercellular matrix from 1000times of magnified microscopic view of skin cross section figure.

EXAMPLE 7

64 micro implements are arranged in a substrate. The micro implement isinstalled just a half-shell cone micro-head of 0.5 mm length and bottomdiameter 0.2 mm made from anhydrous and amorphous Maltose contained 5%cosmetic material of 50% white Titanium oxide and 50% brown iron oxide.Micro implement medication 0.3 mm depth into skin for facial staindisplayed stain reduction and brighter skin seemed recognized around theregion.

EXAMPLE 8

Quadrangular pyramidal micro-head of 0.7 mm length and 0.1 mm bottomside length was contained anhydrous and amorphous oblate spheroidalMaltose chip of 0.02 mm length and 0.01 mm diameter. The chip was madefrom mixing material of 50% Maltose and 50% Hyaluronic acid included 30%albumen which was non-heat resistance limited in 70 degree centigrade.Three micro-heads were installed in three lengths of micro implements of1 mm, 2 mm, and 3 mm. These were used for animal tests of rat, resultingin albumin aggregation in skin. The three aggregation depths werecorresponded to the three length respectively. Albumin resistedtemperature of the micro implement forming process.

EXAMPLE 9

Triangular pyramidal Maltose micro-head of 0.5 mm length and 0.1 mmbottom side length included steel oxide particles in size of average0.003 mm diameter. The micro-head was installed in 1 mm length microimplement and inserted into skin. 1 mG magnetic field was exposed aroundthe particles inserted skin region. The particles were magnetized.Bioactivity around the region was recognized by detecting the magneticfield originated from the particles in skin.

The micro implement with preferred embodiment of the invention and themanufacturing method are useful in medical treatment and beautytreatment. The method belongs to only low cost mechanical field withprocessing a sharp tip as fine as 0.001 mm at largest and includeselements of three dimensional process but does not include a fineprocess of vacuum process and lithography, which have been used as afine technologies. The method can be carried to mass production.

In closing, regarding the exemplary embodiments of the present inventionas shown and described herein, it will be appreciated that apercutaneous implement and method for manufacturing are disclosed.Because the principles of the invention may be practiced in a number ofconfigurations beyond those shown and described, it is to be understoodthat the invention is not in any way limited by the exemplaryembodiments and is able to take numerous forms to do so withoutdeparting from the spirit and scope of the invention. It will also beappreciated by those skilled in the art that the present invention isnot limited to the particular geometries and materials of constructiondisclosed, but may instead entail other functionally comparablestructures or materials, now known or later developed, without departingfrom the spirit and scope of the invention.

Certain embodiments of the present invention are described herein,including the best mode known to the inventor(s) for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor(s) expect skilled artisans to employsuch variations as appropriate, and the inventor(s) intend for thepresent invention to be practiced otherwise than specifically describedherein. Accordingly, this invention includes all modifications andequivalents of the subject matter recited in the claims appended heretoas permitted by applicable law. Moreover, any combination of theabove-described embodiments in all possible variations thereof isencompassed by the invention unless otherwise indicated herein orotherwise clearly contradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

Use of the terms “may” or “can” in reference to an embodiment or aspectof an embodiment also carries with it the alternative meaning of “maynot” or “cannot.” As such, if the present specification discloses thatan embodiment or an aspect of an embodiment may be or can be included aspart of the inventive subject matter, then the negative limitation orexclusionary proviso is also explicitly meant, meaning that anembodiment or an aspect of an embodiment may not be or cannot beincluded as part of the inventive subject matter. In a similar manner,use of the term “optionally” in reference to an embodiment or aspect ofan embodiment means that such embodiment or aspect of the embodiment maybe included as part of the inventive subject matter or may not beincluded as part of the inventive subject matter. Whether such anegative limitation or exclusionary proviso applies will be based onwhether the negative limitation or exclusionary proviso is recited inthe claimed subject matter.

The terms “a,” “an,” “the” and similar references used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Further, ordinal indicators—such as “first,” “second,” “third,”etc.—for identified elements are used to distinguish between theelements, and do not indicate or imply a required or limited number ofsuch elements, and do not indicate a particular position or order ofsuch elements unless otherwise specifically stated. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein is intended merely to better illuminate the presentinvention and does not pose a limitation on the scope of the inventionotherwise claimed. No language in the present specification should beconstrued as indicating any non-claimed element essential to thepractice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

While aspects of the invention have been described with reference to atleast one exemplary embodiment, it is to be clearly understood by thoseskilled in the art that the invention is not limited thereto. Rather,the scope of the invention is to be interpreted only in conjunction withthe appended claims and it is made clear, here, that the inventor(s)believe that the claimed subject matter is the invention.

What is claimed is:
 1. A percutaneous micro implement comprising a micropayload mounted onto an orifice of a stem holder and having a pyramidalmicro head made from water solvable material including a drug with acolumn micro stem integrated under the micro head.
 2. The microimplement of claim 1 wherein the micro head has an external tip radiusof less than 0.01 mm, a length from 0.02 mm to 5 mm, an external radiusof the base from
 0. 01 mm to 1 mm, and being shaped as a pyramidselected from trigonal pyramid, tetragonal pyramid, half shell cone,half shell bullet, cone, bullet, or polygonal pyramid.
 3. The microimplement of claim 2 wherein the micro stem has an external radius from0.01 mm to 1 mm and a length from 0.02 mm to 5 mm, being made from watersolvable material with the same shape as the micro head base in thelower part thereof.
 4. The micro implement of claim 3 wherein the watersolvable material is selected from maltose, pullulan, collagen,hyaluronic acid or polysaccharide or any combination thereof.
 5. Themicro implement of claim 3 wherein the water solvable material isselected from maltose or a mixture with maltose.
 6. The micro implementof claim 3 comprising any of vitamins, hyaluronic acid, collagen,protein, DNA, other drugs, nutrient, supplement, cosmetic materials,antibody drug, in vivo specified pigment, in vivo specified metal, invivo specified metal oxide, in vivo specified magnetic material,biological material, in vivo monitoring material, cell, extra cellularmatrix material, or any combination thereof.
 7. The micro implement ofclaim 2 comprising any of vitamins, hyaluronic acid, collagen, protein,DNA, other drugs, nutrient, supplement, cosmetic materials, antibodydrug, in vivo specified pigment, in vivo specified metal, in vivospecified metal oxide, in vivo specified magnetic material, biologicalmaterial, in vivo monitoring material, cell, extra cellular matrixmaterial, or any combination thereof.
 8. The micro implement of claim 1comprising any of vitamins, hyaluronic acid, collagen, protein, DNA,other drugs, nutrient, supplement, cosmetic materials, antibody drug, invivo specified pigment, in vivo specified metal, in vivo specified metaloxide, in vivo specified magnetic material, biological material, in vivomonitoring material, cell, extra cellular matrix material, or anycombination thereof.
 9. The micro implement of claim 1 wherein the watersolvable material is selected from maltose, pullulan, collagen,hyaluronic acid or polysaccharide or any combination thereof.
 10. Themicro implement of claim 1 wherein the water solvable material isselected from maltose or a mixture with maltose.
 11. The micro implementof claim 1 wherein the stem holder comprises one of maltose, pullulan,hyaluronic acid, cellulose, other saccharide, paper, wood, resin, metalor silk, and having a support with orifice accepting a base of the microstem or having plural supports arranged in a substrate.
 12. A method ofmanufacturing the micro implement according to claim 2 comprising usinga rectangular-solid micro-mold for the pyramidal micro head having aninverse-shaped pyramidal dent coincident with the mold in planes andhaving one or more dents or recesses on the rectangular-solid to form apyramidal and a half-shell pyramidal micro head with a half-shell coneand a half-shell bullet.
 13. A method of manufacturing the microimplement according to claim 3 comprising using a micro-mold for themicro stem with an inverse-shaped prism dent or prism recess to fit themicro stem shape in the surface of a rectangular-solid forming the microstem in any shape of triangular prism, quadrangular prism, column, orhalf-shell column.
 14. A percutaneous micro implement comprising apyramidal micro head containing drug chips.
 15. The micro implement ofclaim 14 comprising any of vitamins, hyaluronic acid, collagen, protein,DNA, other drugs, nutrient, supplement, cosmetic materials, antibodydrug, in vivo specified pigment, in vivo specified metal, in vivospecified metal oxide, in vivo specified magnetic material, biologicalmaterial, in vivo monitoring material, cell, extra cellular matrixmaterial, or any combination thereof.
 16. The micro implement of claim14 wherein the drug chips comprise solidified composite material or amixture of maltose or other saccharide with any drug.
 17. A percutaneousmicro implement comprising a micro-head structure as assembled havingthe shape of a pure or a drug combining two half-shell cones, selectedfrom a pure cone, a cone containing a drug, a combination of purehalf-shell cone and half-shell cone containing a drug, a combination ofa drug containing a half-shell cone and another drug containing ahalf-shell cone, a quadrangular pyramid comprised of a pure pyramid anda drug containing pyramid, a quadrangular pyramid comprised of a drugcontaining pyramid and another drug containing pyramid, a combination ofa drug containing polygonal pyramid and another drug containingpolygonal pyramid configured to be flat on the base when assembled. 18.The micro implement of claim 17 comprising any of vitamins, hyaluronicacid, collagen, protein, DNA, other drugs, nutrient, supplement,cosmetic materials, antibody drug, in vivo specified pigment, in vivospecified metal, in vivo specified metal oxide, in vivo specifiedmagnetic material, biological material, in vivo monitoring material,cell, extra cellular matrix material, or any combination thereof.
 19. Amethod of manufacturing a percutaneous micro implement comprisingmounting a micro payload, integrated by cooling coagulation or dryingsolidification, into an orifice of a stem holder by applying pressure orultrasonic vibration to form a drug material with thermo plasticity ormoist plasticity into a pyramidal or cone shape integrated by a micromold for a micro head, a micro mold for a micro stem, and a holder. 20.A method of manufacturing a percutaneous micro implement comprising asimultaneous three-dimensional mobile function finely adjustable in thethree directions of back and forth, right and left, and up and down andreleasing gradually at speed pitch of 0.001 mm per second vertical to asurface of a micro mold, resulting in a fine releasing process of themolds in forming at least one of a micro head and a micro stem.